CA2058287A1 - Use of the (+) enantiomer of anipamil - Google Patents
Use of the (+) enantiomer of anipamilInfo
- Publication number
- CA2058287A1 CA2058287A1 CA002058287A CA2058287A CA2058287A1 CA 2058287 A1 CA2058287 A1 CA 2058287A1 CA 002058287 A CA002058287 A CA 002058287A CA 2058287 A CA2058287 A CA 2058287A CA 2058287 A1 CA2058287 A1 CA 2058287A1
- Authority
- CA
- Canada
- Prior art keywords
- anipamil
- enantiomer
- acid
- salts
- antiarteriosclerotic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
- 7 - O.Z. 0480/01070 The use of the (+) enantiomer of anipamil Abstract of the disclosure The use of the (+) enantiomer of anipamil and of the salts thereof with physiologically tolerated acids for the preparation of drugs with antiarteriosclerotic properties is described.
Description
O. Z . ~4~0/0107 The use of the ~ ~ ) enantiomer o~ anipamil Z~
Description The invention relates to a novel use of the (+) enantiomer of anipamil (= 1,7-bis-(3-mekhoxyphenyl)-53-methylaza-7-cyano-nonadecane).
Anipamil is disclosed in EP-A 64158. It is stated therein that these compounds (sic) is suitable for the treatment of functional disorders of the cardiovascular system of cardiomyopathies and angiopathies. Further 10indicationR for the substance are h~poxic or ischemic disorders, non-coronarogenic myocardial damage, high blood pressure, disturbances of blood flow, spasms, ulcer and allergic reactions.
Furthermore, US-C 4 777 183 discloses the suita-15bility of anipamil for the preparation of drugs with antiarteriosclerotic properties for the treatment of arteriosclerosis.
It has now been found that ths (~) enantiomer of anipamil has a very good action against arteriosclerosis.
20The invention relates to the use of the (+) enantiomer of anip~nil and of its salts with physiologi-cally tolerated acids ~or the preparation o~ drugs wi~h antiarteriosclerotic propertie~ for the therapy of arteriosclerosi~.
25Arteriosclerosis is a commonly occurring dis-order, doriving from multiactorial causes, of the arterial vessel wall as a consequence o~ which, owing to the formation of atheromas, there i8 constriction of the va~cular system and vascular occlusions. During the 30subsequent course of the disease there are frequently endothelial ruptuxes with hemorrhage~ into the plaque and subsequent thrombosis of the afFected section of vessel (myocardial infarct, stroke).
The compound according to the invention can be 35u~ed to inhibit the formation of atheroma~ in the vesjel wall and the advance of arteriosclerotic lesions already in existence, or to promota the regression thereof.
3~ 7 - 2 ~ O.Z~ 048~/01070 To demonstrate the antiarteriosclerotic ackion, the (+) enantiomer of anipamil i~ administered orally to male rabbits each day for 10 weeks. The animals receive a diet which contains 2% cholesterol to generate arterio-sclerosis. The animals are sacrificed a~ the end of theexperimental period. The aorta is removed between the aor~ic valves and the bifurcation of the aor~a, opened along the median line and stained with 5udan IV. ~he areas with arteriosclerotic lesions in the intima become red in color and are determined by planimetry. The extent of the antiarteriosclerotic action is established by comparing with untreated control animals. ~acemic anipamil is used as comparison substance.
The (+) enantiomer o~ anipamil inhibits the development of arteriosclerosis to the same extent as anipamil (Tab. 1). Howe~er, the compound according to the~
invention is distinctly superior to anipamil for the treatment of arteriosclexosis because it has no cardio-vascular side effects such as, for example, an action lowering blood pres~ure at the same or considerably higher dosage (Tab. 2).
Table 1: ~ntiatherogenic action on rabbits Daily do~ez 30 mg/kg orally `~ Substance No. of ~rea o~ aorta ~
Total area Area with %
a~ ath~x~atous ch~
Challge8 ~
Cbntrol grcup 8 19+0.661) 16~0.91 (~) Enantiomer of anip~l 10 20~0.78 1~+0.12* 27~7.0 Anip~l 20+0.89 11+0.12* 34+6.4 1) X + SX
* p~ 0.01 - 3 - ~.Z. 0480/01070 Table 2: ~ction on the blood pre~sure of conscious spontaneou~ly hypertensive rats (SHR), oral administration Substance E~ 20% (mg/kg)1~ Lowering of Time a~ter blood pressure administration 2 h 6 h 24 h (~) Enantiomer of anipamil > 100 ~ 100 > 100 Anipamil 15.8 15.~ 37.4 Dose which lowers the blood pressure by 20%.
The (+) enantiomer of anipamil and the salts thereo~ can be administered orally or parenterally. The dosage depends on the age, condition and weight of the 15patient and on the mode of administration. As a rule, the daily dose o~ active substance is about 1 to 30, pre-ferably 5 to 25, mg/kg of body content (sic) on oral or rectal administration and 0.05 to 5, preferably 0.5 to 3, mg/kg of body content (sic) on parenteral administration.
20The obtained compound according to the inv~ntion is, where appropriate, converted into the acid addikion salt of a physiologically tolerated acid. A list o conventional physiologically toler~ted acid~ can be found in "Fortschritte dex ~ræneimittelforschung", 1966, 25~ermany, Switzerland, Blrkh~u~er Verlag, vol. 10, pp. 224 to 285 and J. Pharm. Sci., vol. 66 ~1977), pp. 1 to 5.
Hydrochloric acid is preferred.
The acid addition salt is, as a rule, obtained in a manner known per se by mixing the free base or solution 30thereof with th~ appropriate acid or solutions thereof in an organic solvent, for example a lowar alcohol, such as methanol, ethanol or propanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ester ( 5iC ), such aS diethyl ester ~sic~, tetra-35hydrofuran or dioxane. T~ Lmprove crystal deposition, it is pvssible to u~e mixture~ of said solvents. In addition, - 4 - O.Z. 0~80/01070 pharmaceukically acceptable aqueous solution~ of acid addit.ion compounds of (~)-anipamil can be pr0pared by dissolving the free base in an aqueous acid solu~ion~
The (+) enantiomer of anipamil and the salt~
thereof can be used solid or liquid in the conventional pharmaceutical administration forms, eg. in the form of tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or metered aerosols. These are prepared in the conven-tional manner. The active substances can moreover be administered with the conventional pharmaceutical auxi~
liaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersan~s, emulsifiers, solvents, retarding agents and/or antioxidants (cf. H. Sucker et al.: Pharmazeutische Technologie, Theime-Verl~g, Stuttgart (1978). The formulations obtained in this way normally contain ~he active substance in an amount of from 0.1 to 99% by weight.
Example 1 r~ablets of the f411Owing composition are com-pressed in a tablet press in a conventional manner:
80 mg of t~) enan-tiomer of anipamil 235 mg of corn staxch 27 mg of gelatin 90 mg of lacto~e ~.5 mg of Aerosil~ (chemically pure silica in submicro~copically fine distributiorl) 13.5 mg of potato starch (as 6% strength paste) 3~ Example 2 Sugar-coated tablets of the following composition are prepared in a conventional manner:
40 mg of (+) enantiomer of anipamil 120 mg of core composition 120 mg of sugar-coating composition The core composition i5 composed of 9 parts of corn starch, 3 par~s of lactose and 1 part of 60:40 - 5 - O.Z. 0480/01070 vinylpyrroLidone/vinyl acetate copolymer (c~. Pharm. Ind.
1962, 586). The sugar-coating composition is composed of 5 parts of sucro~e, 2 parts o~ corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets prepared in this way are subsequently provided with an enteric coating.
Example 3 10 g of (+) enantiomer of anipamil are dissolved in 5000 ml of water with the addition of NaC1 and adjus-ted ~o pH 6.0 so that a solu~ion which is isotonic withblood is produced.
Description The invention relates to a novel use of the (+) enantiomer of anipamil (= 1,7-bis-(3-mekhoxyphenyl)-53-methylaza-7-cyano-nonadecane).
Anipamil is disclosed in EP-A 64158. It is stated therein that these compounds (sic) is suitable for the treatment of functional disorders of the cardiovascular system of cardiomyopathies and angiopathies. Further 10indicationR for the substance are h~poxic or ischemic disorders, non-coronarogenic myocardial damage, high blood pressure, disturbances of blood flow, spasms, ulcer and allergic reactions.
Furthermore, US-C 4 777 183 discloses the suita-15bility of anipamil for the preparation of drugs with antiarteriosclerotic properties for the treatment of arteriosclerosis.
It has now been found that ths (~) enantiomer of anipamil has a very good action against arteriosclerosis.
20The invention relates to the use of the (+) enantiomer of anip~nil and of its salts with physiologi-cally tolerated acids ~or the preparation o~ drugs wi~h antiarteriosclerotic propertie~ for the therapy of arteriosclerosi~.
25Arteriosclerosis is a commonly occurring dis-order, doriving from multiactorial causes, of the arterial vessel wall as a consequence o~ which, owing to the formation of atheromas, there i8 constriction of the va~cular system and vascular occlusions. During the 30subsequent course of the disease there are frequently endothelial ruptuxes with hemorrhage~ into the plaque and subsequent thrombosis of the afFected section of vessel (myocardial infarct, stroke).
The compound according to the invention can be 35u~ed to inhibit the formation of atheroma~ in the vesjel wall and the advance of arteriosclerotic lesions already in existence, or to promota the regression thereof.
3~ 7 - 2 ~ O.Z~ 048~/01070 To demonstrate the antiarteriosclerotic ackion, the (+) enantiomer of anipamil i~ administered orally to male rabbits each day for 10 weeks. The animals receive a diet which contains 2% cholesterol to generate arterio-sclerosis. The animals are sacrificed a~ the end of theexperimental period. The aorta is removed between the aor~ic valves and the bifurcation of the aor~a, opened along the median line and stained with 5udan IV. ~he areas with arteriosclerotic lesions in the intima become red in color and are determined by planimetry. The extent of the antiarteriosclerotic action is established by comparing with untreated control animals. ~acemic anipamil is used as comparison substance.
The (+) enantiomer o~ anipamil inhibits the development of arteriosclerosis to the same extent as anipamil (Tab. 1). Howe~er, the compound according to the~
invention is distinctly superior to anipamil for the treatment of arteriosclexosis because it has no cardio-vascular side effects such as, for example, an action lowering blood pres~ure at the same or considerably higher dosage (Tab. 2).
Table 1: ~ntiatherogenic action on rabbits Daily do~ez 30 mg/kg orally `~ Substance No. of ~rea o~ aorta ~
Total area Area with %
a~ ath~x~atous ch~
Challge8 ~
Cbntrol grcup 8 19+0.661) 16~0.91 (~) Enantiomer of anip~l 10 20~0.78 1~+0.12* 27~7.0 Anip~l 20+0.89 11+0.12* 34+6.4 1) X + SX
* p~ 0.01 - 3 - ~.Z. 0480/01070 Table 2: ~ction on the blood pre~sure of conscious spontaneou~ly hypertensive rats (SHR), oral administration Substance E~ 20% (mg/kg)1~ Lowering of Time a~ter blood pressure administration 2 h 6 h 24 h (~) Enantiomer of anipamil > 100 ~ 100 > 100 Anipamil 15.8 15.~ 37.4 Dose which lowers the blood pressure by 20%.
The (+) enantiomer of anipamil and the salts thereo~ can be administered orally or parenterally. The dosage depends on the age, condition and weight of the 15patient and on the mode of administration. As a rule, the daily dose o~ active substance is about 1 to 30, pre-ferably 5 to 25, mg/kg of body content (sic) on oral or rectal administration and 0.05 to 5, preferably 0.5 to 3, mg/kg of body content (sic) on parenteral administration.
20The obtained compound according to the inv~ntion is, where appropriate, converted into the acid addikion salt of a physiologically tolerated acid. A list o conventional physiologically toler~ted acid~ can be found in "Fortschritte dex ~ræneimittelforschung", 1966, 25~ermany, Switzerland, Blrkh~u~er Verlag, vol. 10, pp. 224 to 285 and J. Pharm. Sci., vol. 66 ~1977), pp. 1 to 5.
Hydrochloric acid is preferred.
The acid addition salt is, as a rule, obtained in a manner known per se by mixing the free base or solution 30thereof with th~ appropriate acid or solutions thereof in an organic solvent, for example a lowar alcohol, such as methanol, ethanol or propanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ester ( 5iC ), such aS diethyl ester ~sic~, tetra-35hydrofuran or dioxane. T~ Lmprove crystal deposition, it is pvssible to u~e mixture~ of said solvents. In addition, - 4 - O.Z. 0~80/01070 pharmaceukically acceptable aqueous solution~ of acid addit.ion compounds of (~)-anipamil can be pr0pared by dissolving the free base in an aqueous acid solu~ion~
The (+) enantiomer of anipamil and the salt~
thereof can be used solid or liquid in the conventional pharmaceutical administration forms, eg. in the form of tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or metered aerosols. These are prepared in the conven-tional manner. The active substances can moreover be administered with the conventional pharmaceutical auxi~
liaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersan~s, emulsifiers, solvents, retarding agents and/or antioxidants (cf. H. Sucker et al.: Pharmazeutische Technologie, Theime-Verl~g, Stuttgart (1978). The formulations obtained in this way normally contain ~he active substance in an amount of from 0.1 to 99% by weight.
Example 1 r~ablets of the f411Owing composition are com-pressed in a tablet press in a conventional manner:
80 mg of t~) enan-tiomer of anipamil 235 mg of corn staxch 27 mg of gelatin 90 mg of lacto~e ~.5 mg of Aerosil~ (chemically pure silica in submicro~copically fine distributiorl) 13.5 mg of potato starch (as 6% strength paste) 3~ Example 2 Sugar-coated tablets of the following composition are prepared in a conventional manner:
40 mg of (+) enantiomer of anipamil 120 mg of core composition 120 mg of sugar-coating composition The core composition i5 composed of 9 parts of corn starch, 3 par~s of lactose and 1 part of 60:40 - 5 - O.Z. 0480/01070 vinylpyrroLidone/vinyl acetate copolymer (c~. Pharm. Ind.
1962, 586). The sugar-coating composition is composed of 5 parts of sucro~e, 2 parts o~ corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets prepared in this way are subsequently provided with an enteric coating.
Example 3 10 g of (+) enantiomer of anipamil are dissolved in 5000 ml of water with the addition of NaC1 and adjus-ted ~o pH 6.0 so that a solu~ion which is isotonic withblood is produced.
Claims (2)
1. The use of the (+) enantiomer of anipamil and of the salts thereof with physiologically tolerated acids for the therapy of arteriosclerosis.
2. The use of the (+) enantiomer of anipamil and of the salts thereof with physiologically tolerated acids for the preparation of drugs with antiarteriosclerotic action.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3928287A DE3928287A1 (en) | 1989-08-26 | 1989-08-26 | USE OF THE (+) - ENANTIOMER OF ANIPAMIL |
| DEP3928287.2 | 1989-08-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2058287A1 true CA2058287A1 (en) | 1991-02-27 |
Family
ID=6387968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002058287A Abandoned CA2058287A1 (en) | 1989-08-26 | 1990-08-22 | Use of the (+) enantiomer of anipamil |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0489043B1 (en) |
| JP (1) | JPH04507246A (en) |
| CA (1) | CA2058287A1 (en) |
| DE (2) | DE3928287A1 (en) |
| WO (1) | WO1991002524A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06508836A (en) * | 1991-06-26 | 1994-10-06 | セプラコア，インコーポレーテッド | Methods and compositions for the treatment of emesis, nausea and other disorders using optically pure R(+) ondansetron |
| CA2124445A1 (en) * | 1991-11-26 | 1993-06-10 | James W. Young | Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine |
| CA2371822A1 (en) | 1999-03-01 | 2000-09-08 | Sepracor Inc. | Methods for treating apnea and apnea disorders using optically pure r(+)ondansetron |
| IL254802A0 (en) | 2017-09-29 | 2017-12-31 | Medimop Medical Projects Ltd | Dual vial adapter assemblages with twin vented female vial adapters |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3634389A1 (en) * | 1986-10-09 | 1988-04-21 | Knoll Ag | USE OF ANIPAMIL |
| DE3635931A1 (en) * | 1986-10-22 | 1988-04-28 | Basf Ag | ACTIVE SUBSTANCES FOR PREVENTING TUMOR METASAS |
-
1989
- 1989-08-26 DE DE3928287A patent/DE3928287A1/en not_active Withdrawn
-
1990
- 1990-08-22 WO PCT/EP1990/001398 patent/WO1991002524A1/en active IP Right Grant
- 1990-08-22 CA CA002058287A patent/CA2058287A1/en not_active Abandoned
- 1990-08-22 JP JP2511594A patent/JPH04507246A/en active Pending
- 1990-08-22 DE DE90912145T patent/DE59004528D1/en not_active Expired - Fee Related
- 1990-08-22 EP EP90912145A patent/EP0489043B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04507246A (en) | 1992-12-17 |
| DE59004528D1 (en) | 1994-03-17 |
| DE3928287A1 (en) | 1991-02-28 |
| WO1991002524A1 (en) | 1991-03-07 |
| EP0489043B1 (en) | 1994-02-02 |
| EP0489043A1 (en) | 1992-06-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |